The studies proposed in this project continue to follow the major aspects of the original research plan. Although alcohol, barbiturates and various narcotics (e.g., morphine, heroin, and methadone are known to affect the cardiovascular system, very little definitive work has been done in relation to their effects on peripheral blood vessels. The studies proposed in this project will continue to focus on in-vivo (microciruclation) and isolated mammalian and human blood vessels and will: 1. Determine whether acute administration of ethanol, barbiturates and/or narcotics have direct musculotropic actions on vascular smooth muscle. 2. Determine the site(s) of action of these drugs in the microcirculation (e.g., arterioles, metarterioles, venules or precapillary sphincters). 3. Determine whether these drugs affect blood vessels by virtue of indirect actions. 4. Determine whether tolerance and/or addiction to these narcotic drugs, barbiturates and alcohol change the characteristics of vascular smooth muscle. 5. Having documented the foregoing as a frame of reference, ionic and biochemical mechanisms of possible drug action will be explored. 6. Explore sex hormones and aging in relation to the peripheral circulatory actions of alcohol, barbiturates and narcotics.